DESCRIPTION: (Applicant?s Description) Unresectable primary lung cancer remains one of the most formidable problems in oncology. Despite the use of chemotherapy and radiation therapy in combined modality protocols, local control rates are less than 20 percent. Locally advanced non-small cell lung cancer (NSCLC) represents an excellent therapeutic target and model system for a clinical protocol involving gene transfer. A large volume of preclinical and the phase I clinical trial data for an adenoviral vector expressing wildtype p53 (Ad-p53) support the initiation of a clinical trial to test the hypothesis that: (1) over-expression of wild-type p53 in NSCLC cells will enhance sensitivity to external beam ionizing radiation, and (2) that the combination therapy will improve local control and ultimately survival in NSCLC. The design of this trial will take into consideration the possibility that adverse events related to the combination of Ad-p53 and radiation not seen with Ad-p53 alone could occur and will assess this first with a small run-in dose escalation study. This will be followed by a phase II clinical trial to address the following specific aims. Aim 1: To determine if the intralesional administration of Ad-p53 in conjunction with primary radiation therapy increases local tumor control in patients with NSCLC, and in follow-up randomized clinical trial, to determine if induction chemotherapy, radiation therapy, and intralesional Ad-p53 increased local tumor control and survival compared to induction chemotherapy and radiation therapy only. Aim 2: To determine the qualitative and quantitative toxicity and reversibility of toxicity following intralesional administration of Ad-p53 in conjunction with radiation therapy in patients with NSCLC. Aim 3: To conduct laboratory experiments to validate that the vectors proposed, Adv-p53 and others function to sensitize cells derived from various human tumors to radiation both in vitro and in vivo. Aim 4: To conduct mechanistic studies to determine the biochemical pathways activated in cells following gene therapy responsible for restoring apoptosis propensity and radiosensitization.